Mucositis is defined as inflammation and ulceration of the mucous membranes, and is a common dose-limiting toxic reaction to chemotherapy and radiotherapy. The affected mucous membrane may be in oral tissues, lung tissues, intestines or other organs. For a general background on mucositis, see Sonis et al., Cancer Suppl., vol. 100, no. 9, pp. 1995-2025 (2004).
Among other radiation- and/or chemical-induced toxicity in non-malignant tissues, mucositis is a common and potentially serious side effect. In fact, oral mucositis has been identified as the most debilitating side effect of anticancer therapy by patients who experienced it while undergoing myelotoxic therapy for hematopoietic stem cell transplantation. Patients suffering from severe oral mucositis may find daily activities such as eating, drinking, swallowing, and talking difficult or impossible. When treated to ameliorate and/or prevent radiation- and/or chemical-induced toxicity in non-malignant tissues, patients receiving therapeutic radiation and/or chemical treatments may experience a higher quality of life and thereby remain on their therapeutic regimen so that the therapeutic effect may be achieved or possibly receive a more demanding and more effective therapeutic regimen.
In mucositis, the degree of injury to mucosal tissue is directly related to the type, dose, or dose intensity of the radiotherapy and/or chemotherapy regimens employed. Non-limiting examples of drugs that can result in mucositis include: anthracyclines (such as daunorubicin, doxorubicin, pirubicin, idarubicin and mitoxantrone), methotrexate, dactinomycin, bleomycin, vinblastine, cytarabin, fluorouracil, mitramycine, taxanes (such as docetaxel and paclitaxel), ifosfamide/eoposide, irinotecan, platinum, as well as combinations including one or more of these drugs.
Non-therapeutic radiation and/or chemical exposure, as may happen from accidents, acts of war, acts of civilian terrorism, space flights, or rescue and clean-up operations can also result in mucositis. In these scenarios the effects of radiation in the hematopoietic system and the gastrointestinal tract are critical.
Several agents have been investigated in order to find optimal management principles for mucositis and even though some agents have shown some prophylactic effect, no agent has been shown to be efficient in all settings. Thus, a need exists for methods of treating and/or preventing mucositis regardless of its cause.
Vitamin D is a fat-soluble vitamin essential as a positive regulator of calcium homeostasis. The hormonally active form of vitamin D is 1α,25-dihydroxyvitamin D3, also known as calcitriol. Calcitriol is a steroid hormone synthesized from dietary precursors. Dietary 7-dehydrocholesterol is converted to vitamin D3 by ultraviolet light absorbed through the skin. Vitamin D3 is hydroxylated at the 25 position by the liver and at the 1 position by the kidneys, converting it to the biologically active form, calcitriol. 1α-hydroxyvitamin D3, also known as la-calcidol, and 25-hydroxyvitamin D3, also known as calcifediol, are monohydroxylated vitamin D3 and may be converted to calcitriol upon hydroxylation by the liver and kidney, respectively. Specific nuclear receptors for active vitamin D compounds have been discovered in cells from diverse organs not involved in calcium homeostasis. Thus, in addition to influencing calcium homeostasis, active vitamin D compounds have been implicated in variety of biological processes.
In connection with the treatment of hyperproliferative diseases, it has been shown that the problem of systemic hypercalcemia can be overcome by “high dose pulse administration” (HDPA) of a sufficient dose of an active vitamin D compound to give an antiproliferative effect while avoiding the development of severe symptomatic hypercalcemia. According to U.S. Pat. No. 6,521,608, the active vitamin D compound may be administered no more than every three days, for example, once a week at a dose of at least 0.12 μg/kg per day (8.4 μg in a 70 kg person). Pharmaceutical compositions used in the HDPA regimen of U.S. Pat. No. 6,521,608 comprise 5-100 μg of active vitamin D compound and may be administered in the form for oral, intravenous, intramuscular, topical, transdermal, sublingual, intranasal, intratumoral, or other preparations.